Effects of all-trans-retinoic acid incorporated into low-density lipoprotein on invasive properties of multidrug-resistant MCF-7 spheroids.

M Affoué, M G Akeli, N Gueddari, J C Jardillier, C Madoulet
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引用次数: 3

Abstract

Cultured cells grown as spheroids provide an in vitro model that is closer to an in vivo tumour than conventional monolayer techniques. Previous work from our laboratory has demonstrated that spheroids formed from multidrug-resistant MCF-7 cells exhibit invasive characteristics which were not present in their sensitive counterparts. The treatment of these spheroids by all-trans-retinoic acid (ATRA), a potent inducer of in vitro and in vivo differentiation, decreases their proteolytic activity and ability to invade Matrigel-coated filters. The efficiency of ATRA is enhanced by its incorporation into low-density lipoprotein (LDL) (LDL-ATRA). Indeed, invasion through a reconstituted basement membrane was reduced by 73% with 10(-6) M ATRA and 3 x 10(-8) M LDL-ATRA. Furthermore, inhibition of invasion was correlated with a decrease in several factors: (1) secreted matrix metalloproteinase-9 and enzymes degrading type IV collagen and Matrigel films, and (2) tissue plasminogen activator. The results observed were found with a concentration of LDL-ATRA 30 times lower than that of ATRA. This could be due to the protective effect of LDL and to a better targeting of cancer cells through their LDL receptors. LDL-ATRA may therefore represent a new and potent inhibitor of invasion that could be developed for clinical trials.

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低密度脂蛋白掺入全反式维甲酸对多药耐药MCF-7球体侵袭特性的影响
作为球体生长的培养细胞提供了比传统单层技术更接近体内肿瘤的体外模型。我们实验室之前的工作已经证明,由耐多药MCF-7细胞形成的球体表现出侵袭性特征,而这些特征在敏感的MCF-7细胞中不存在。全反式维甲酸(ATRA)是一种有效的体外和体内分化诱导剂,它对这些球体的处理降低了它们的蛋白水解活性和侵入基质涂层过滤器的能力。ATRA的效率通过其掺入低密度脂蛋白(LDL-ATRA)而提高。事实上,使用10(-6)M ATRA和3 × 10(-8) M LDL-ATRA,通过重建基膜的侵袭减少了73%。此外,侵袭抑制与以下几个因素的减少有关:(1)分泌基质金属蛋白酶-9和降解IV型胶原和Matrigel膜的酶,以及(2)组织纤溶酶原激活物。结果发现LDL-ATRA浓度比ATRA低30倍。这可能是由于低密度脂蛋白的保护作用,以及通过低密度脂蛋白受体更好地靶向癌细胞。因此,LDL-ATRA可能是一种新的有效的侵袭抑制剂,可以用于临床试验。
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